Angiogenesis plays an important role in many diseases, including atherosclerosis, diabetic retinopathy, and cancer. Experiments in transgenic mice have demonstrated essential, nonoverlapping roles for the endothelium-specific receptor tyrosine kinases (RTKs) Tie-1 and Tek (also known as Tie-2) in embryonic vascular development. Despite structural similarities, phenotypic differences between the receptor knockouts suggest that these receptors have distinct functions that are likely mediated by differences in downstream signaling pathways. We hypothesize that elucidation of divergent """"""""angiogenic"""""""" signaling pathways downstream of Tek and Tie-1 will clarify their roles in vascular growth and development and could lead to the design of therapeutic interventions for disease in which angiogenesis play a role. To address this hypothesis, the specific aims of this proposal are to: 1) Identify endothelial signal transduction molecules downstream of the Tek and Tie-1 receptors; 2) Characterize the interaction of known and novel signaling molecules with Tek and Tie-1; 3) Determine the specific endothelial cellular responses mediated by the signaling proteins identified in Specific Aim 1. Accomplishing these specific aims will provide an understanding of how growth and differentiation signals are transduced in endothelial cell to mediate the biologic responses necessary for vascular growth. This knowledge will help unravel the basic mechanisms of pathologic angiogenesis and allow the targeting of rational therapeutic interventions in a variety of diseases. Additionally, studies in this proposal, complemented by supplementary didactic training in molecular biology, will lay the groundwork for the applicant to develop a career as an independent investigator in the study of signal transduction in the vessel wall as it relates to cardiovascular physiology and pathophysiology.
